Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

Adenosine can induce hypothermia, as previously demonstrated for adenosine A(1) receptor (A(1)AR) agonists. Here we use the potent, specific A(3)AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A(3)AR. The hypothermic effect of A(3)AR agonists is independent of A(1)AR activation, as the effect was fully intact in mice lacking A(1)AR but abolished in mice lacking A(3)AR. A(3)AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A(3)AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A(3)AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H-1 (but not H-2 or H-4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A(3)AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A(3)AR agonists act on peripheralmast cells, causing histamine release, which stimulates central histamine H-1 receptors to induce hypothermia. This mechanism suggests that A(3)AR agonists will probably not be useful for clinical induction of hypothermia.